Systems Approaches for Rationally Designing Innate Immune Therapies

TAM (Tyro3, AXL, MerTK) receptors are implicated in resistance to targeted therapies and metastasis via tumor cell-intrinsic effects, while more recent evidence has implicated the same receptors expressed on immune cells as a potentially effective therapeutic targets in many cancers. Outside of cancer, these receptors have been implicated in a number of diseases involving immunological dysregulation including lupus, rheumatoid arthritis, endometriosis, viral infection, and asthma. Rationally targeting these receptors, and even understanding how existing therapies function, has been limited by poor understanding of how the receptors are activated.

As efferocytosis receptors, a principal function of TAMs is to drive phagocytosis of phosphatidylserine-presenting extracellular debris via their ligands. Consequently, studying the receptors requires taking into account receptor function, ligand engagement, and the role of lipid vesicles. Work from the lab recently proposed, using a combination of modeling and experimental validation, that spatially-defined ligand presentation is vital to activation of these receptors. Spatial patterning underlies nearly all signaling processes. However, developing models incorporating spatial signaling aspects has been hampered both by difficulties in computationally accounting for these factors as well as experimentally manipulating them during model training and validation. This, therefore, represents a rich area for both modeling and experimental methodological development.

In many cancers, a subset of tumor cells overexpress AXL, making them invasive and resistant to therapy. TAM receptor activation within dendritic cells potently inhibits the innate immune response. T cell release of ProS further dampens the immune response. Activation of TAMs inhibits NK cell-mediated lysis. Each of these cell populations express distinct and dynamic combinations of TAM receptor, likely modulating functional changes in microenvironmental response.

To expand upon this initial model, we have been and will continue modeling the activation and subsequent phenotypic effects of TAM receptors within tumor and immune cells. Currently, we are quantitating the pattern of expression and measuring kinetic binding parameters necessary to simulate activation of the TAM receptors across many immune cell types. To rapidly develop models of receptor activation, we are rigorously accounting for the uncertainty in our models using Bayesian methods. We are taking advantage of our deep experimental and computational integration by utilizing, for example, a panel of receptor fragments, each with distinct binding properties. These represent unique TAM-targeted agents with therapeutic potential and specific inhibition profiles toward certain cell populations or activation mechanisms. At the same time, their specific effects will provide novel interventions to help deconvolve the pleiotropic roles of these receptors in vivo.

More broadly, maximizing the potential of immune-targeted therapies will require an improved, multi-scale understanding of tumor-immune interaction from the molecular level to that of cell-cell interactions. Like TAMs, many receptors such as the Fc family and complement receptor are poorly understood both in their proximal activation and their downstream signaling effects, have simultaneous roles in signaling and trafficking, are activated through clustering as opposed to strictly receptor-ligand interaction, and derive specificity through the combination of activated species. Thus, TAM receptors represent a valuable prototype for studying immune receptor function on a systems level more generally. Indeed, we are beginning to take a similar approach targeting IgG effector function across cell populations using multivariate models of FcγR-IgG interaction.